PFKFB3驱动的糖酵解在重症急性胰腺炎中的调控作用及分子机制研究

Severe Acute pancreatitis (SAP) is a common and devastating inflammatory disorder of the pancreas, with very high mortality. However, there are still no effective treatments available for SAP. It is important to study the early events happened in acinar cells and discover novel therapeutic targets, which will significantly improve the survival rate and the prognosis of the SAP patients. Previous studies have shown that the pathogenesis of SAP is often accompanied by the impaired mitochondrial function of acinar cells, collapsed oxidation phosphorylation metabolism, insufficient ATP production, and resulting in Ca2+ overload and subsequent necrosis of acinar cells. However, the changes and the roles of the glycolysis pathway during the processes of AP/SAP are still unclear. We hypothesize that the glycolysis pathway is activated during SAP to compensate for the lack of ATP caused by impaired mitochondrial function, which plays inhibitory effects on SAP-related inflammatory damages. Our preliminary results have shown that the expression of the key enzyme of glycolysis PFKFB3 is significantly upregulated during the process of AP/SAP, and thus the lactic acid level increased sharply in the mouse models. 3PO, an inhibitor targeting PFKFB3 enzyme activity aggravates the inflammatory damage of caerulein-induced AP and TCLS-SAP mouse models. PFKFB3 heterozygous knockout mice also show more severe AP symptoms. Taken together, our current project will explore the role of PFKFB3-driven glycolysis in SAP and elucidate the relevant molecular mechanisms, which will provide novel targets and strategies for the treatment of SAP including alcoholic pancreatitis and gallstone pancreatitis.

重症急性胰腺炎(SAP)是临床上常见的危重炎症性疾病、死亡率较高。研究SAP过程中腺泡细胞的早期事件、寻找新的防治靶点对提高SAP病人生存率、改善患者预后具有重要意义。以往的研究表明SAP发病过程常伴随腺泡细胞线粒体功能受损、氧化磷酸化能力下降、ATP产能不足、导致Ca2+超载及腺泡细胞坏死。糖酵解在AP/SAP过程中的变化及作用尚不明确。我们推测糖酵解在SAP过程中被激活以补偿线粒体功能受损导致的ATP产量不足，从而对SAP相关的炎症损伤有一定的缓解作用。我们的预实验结果表明，AP发病过程中糖酵解关键酶PFKFB3表达上调、糖酵解产物乳酸水平上升。 PFKFB3酶活性抑制剂3PO以及PFKFB3基因缺失均能加重水肿型AP和胆石性SAP小鼠模型的炎症损伤。本项目将探讨腺泡细胞中PFKFB3驱动的糖酵解在SAP中的调控作用并阐明相关分子机制，为酒精性和胆石性SAP的治疗提供新的靶点和策略。

急性胰腺炎(Acute Pancreatitis, AP)是医院最常见的胃肠道急腹症之一，了解其病理机制对开发新的治疗方案至关重要。 本项目研究表明，在AP进展过程中磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3 (PFKFB3)表达水平升高。 胰腺组织特异性敲除PFKFB3对棕榈油酸联合乙醇诱导的急性酒精性胰腺炎模型具有保护作用。PFKFB3通过与肌醇1,4,5-三磷酸受体(IP3R)之间的直接相互作用进而调控胰腺腺泡细胞内钙离子稳态是介导这一保护作用的主要关键事件。PFKFB3敲除可改善棕榈油酸和乙醇诱导的急性酒精性胰腺炎严重程度，且该作用不依赖其在糖酵解途径中的调控作用。本项目为PFKFB3在急性胰腺炎严重程度调节中的新作用提供了证据。敲除PFKFB3 在急性酒精性胰腺炎进展过程中具有保护作用。结合全基因组学分析、 生物化学和分子机制研究，我们将PFKFB3与IP3R的相互作用定义为介导这一现象的关键事件。进一步的研究表明 PFKFB3和 IP3R之间的相互作用可通过改变腺泡细胞内钙稳态来加重FAEE-SAP的严重程度。因此，我们的研究结果支持了一种新的 PFKFB3 驱动的AP病理生物学调控机制，提示PFKFB3作为防治酒精性急性胰腺炎的潜在新靶点，并为开发相关治疗药物提供理论依据。

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